This proposal seeks renewal of funding to support and extend a successful interdisciplinary predoctoral program that prepares students with strong backgrounds in quantitative physical sciences to conceptualize, conduct, and direct independent research in molecular biophysics and structural biology. The Molecular Biophysics and Structural Biology (MBSB) graduate program places a strong emphasis on inter- disciplinary, collaborative research in an environment where the practical human health consequences of research are appreciated and contribute to guiding and driving basic research. The training faculty has expanded to 54 independent investigators spread over 14 departments within the School of Medicine and the Faculty of Arts and Sciences at the University of Pittsburgh, and within the Mellon College of Science at Carnegie Mellon University. Senior researchers have strong records in graduate training, funding, and publications, and the program also includes junior faculty who bring new ideas and technical expertise to the group. The research programs of training faculty emphasize not only characterization of biomolecular phenomena but also development of new methodologies. The relationship between physical methods and biological understanding is a key aspect of the curriculum. Research is focused on core areas at the forefront of biomolecular science, including membrane proteins, protein-protein interactions and oligomeric complexes, nucleic acid structure and protein-nucleic acid interactions, poorly structured protein elements, protein misfolding and aggregation, and small molecule ligand-protein interactions. The training program includes a first-year core curriculum featuring an introduction to biophysical instrumentation and methods, how these are used to address specific molecular questions, an introduction to theory and simulation of biomolecular behavior, and courses on statistical analysis, computer programming and ethics. Students' abilities to synthesize and creatively utilize what they have learned in the classroom are tested in a qualifying exam that requires them to construct and defend a research proposal not related to their own laboratory work. After passing this exam students move on to develop and pursue their thesis project. Students are required to participate in a weekly journal/data club and to attend a Molecular Biophysics seminar series featuring invited local and national speakers. An annual program Symposium is held with invited speakers and student participation through talks and posters. This renewal builds on the successes of the MBSB program and its unique and rich blend of faculty expertise favoring cross-disciplinary and co-mentored thesis projects to prepare students for success in the modern research environment. We are requesting funds to continue support for four traineeships and extend this to the six originally envisioned with the goal of training a new generation of molecular biophysicists and structural biologists who will be leaders in future efforts to understand normal and abnormal human biology at the physical and molecular level.